[go: up one dir, main page]

EP3675845B1 - Nouveaux modulateurs du récepteur de l'acide gamma-aminobutyrique de type a destinés aux troubles de l'humeur - Google Patents

Nouveaux modulateurs du récepteur de l'acide gamma-aminobutyrique de type a destinés aux troubles de l'humeur Download PDF

Info

Publication number
EP3675845B1
EP3675845B1 EP18852438.3A EP18852438A EP3675845B1 EP 3675845 B1 EP3675845 B1 EP 3675845B1 EP 18852438 A EP18852438 A EP 18852438A EP 3675845 B1 EP3675845 B1 EP 3675845B1
Authority
EP
European Patent Office
Prior art keywords
compound
depression
deuterated
gaba
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP18852438.3A
Other languages
German (de)
English (en)
Other versions
EP3675845A1 (fr
EP3675845A4 (fr
Inventor
Scott Thompson
Adam VAN DYKE
Craig Thomas
Patrick Morris
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Maryland Baltimore
University of Maryland College Park
US Department of Health and Human Services
Original Assignee
University of Maryland Baltimore
University of Maryland College Park
US Department of Health and Human Services
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Maryland Baltimore, University of Maryland College Park, US Department of Health and Human Services filed Critical University of Maryland Baltimore
Publication of EP3675845A1 publication Critical patent/EP3675845A1/fr
Publication of EP3675845A4 publication Critical patent/EP3675845A4/fr
Application granted granted Critical
Publication of EP3675845B1 publication Critical patent/EP3675845B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to the fields of neurology, psychiatry, pharmacology and medicine. Specifically, the invention relates to compositions and methods for treating, preventing or ameliorating depression and/or other psychiatric and neurological conditions using negative allosteric modulators (NAM) selective for gamma-aminobutyric acid (GABA) receptors containing alpha5 subunits that have been deuterated at key positions to enhance their medicinal value as fast-acting antidepressant compounds.
  • NAM negative allosteric modulators
  • GABA gamma-aminobutyric acid
  • the deuterated compounds have enhanced properties because the deuteration has been performed specifically to prolong their half-life in the human body.
  • GABA A R The gamma-aminobutyric acid A receptor
  • GABA A Rs are found in all organisms with a central nervous system. Because of their wide distribution within the nervous system of mammals, they play a role in virtually all brain functions.
  • the endogenous ligand of the GABA A R is gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.
  • GABA A Rs are heteropentameric, ligand-gated ion channels. Nineteen GABA A receptor subunits have been identified to date.
  • GABA A receptors contain ⁇ , ⁇ , and ⁇ 2 subunits in a 2:2:1 stoichiometry.
  • the primary activation site of the GABA A R is the binding site for GABA and for several drugs, including muscimol, gaboxadol, and bicuculline.
  • the interface between adjacent ⁇ 2 and ⁇ subunits form the benzodiazepine site, an allosteric modulator of channel gating.
  • the identity of the ⁇ subunit determines the pharmacological profile of this site.
  • Receptors containing ⁇ 1, ⁇ 2, or ⁇ 3 subunits are potentiated by zolpidem, a benzodiazepine type 1 agonist, whereas receptors containing ⁇ 5 subunits are essentially insensitive to zolpidem. Drugs binding at this site can affect the ability of GABA to activate the GABA A R, including positive allosteric modulators that promote function and negative allosteric modulators that decrease function. Recent studies have shown that ⁇ 1 subunits mediate the sedative, anticonvulsant and amnestic effects of benzodiazepines preferentially, whereas the ⁇ 2 and ⁇ 3 subunits mediate their anxiolytic effects.
  • Partial inverse agonists offer the advantage of a wider therapeutic concentration range and a lower likelihood of producing anxiety or epileptiform discharge, in specific embodiments of the disclosure.
  • ⁇ 5-subunit mRNA is highly expressed in the pyramidal cells of the hippocampus and cortex (Allen Brain Atlas) and ⁇ 5-containing GABA A receptors are localized in the dendrites of hippocampal CA1 pyramidal cells at synaptic and extrasynaptic sites. Because disinhibition promotes induction of long-term potentiation (LTP), and because of their selective forebrain localization, drugs that selectively inhibit ⁇ 5-containing receptors are being developed as cognitive enhancers. It has been shown, for example, that partial inverse agonists of ⁇ 5-containing GABA A receptors enhance associative memory acquisition in hippocampal-dependent learning tasks.
  • LTP long-term potentiation
  • SSRls selective serotonin reuptake inhibitors
  • Those currently under development display a number of side effects that limit their clinical utility, such as liability for abuse and tendency to induce psychosis-like responses.
  • Alternative medications for depression do exist, however many of these suffer from the same need for prolonged treatment before efficacy, and many of these also are ineffective or only partially effective. Therefore, there is a need to identify new drugs that can be used to treat depressive disorders and reduce the incidence of suicide on a worldwide basis.
  • GABA A R The gamma-aminobutyric acid A receptor
  • GABA gamma-aminobutyric acid
  • the primary activation site of the GABA A R is the binding site for GABA and for several drugs, including muscimol, gaboxadol, and bicuculline.
  • a second binding site on GABA A R is the so-called benzodiazepine receptor site. Drugs binding at this site can affect (promote or impair) the ability of GABA to activate the GABA A R.
  • GABA A Rs are found in all organisms with a central nervous system. Because of their wide distribution within the nervous system of mammals, they play a role in virtually all brain functions.
  • the present invention relates to compositions and methods for the treatment of certain medical conditions, including depression-related disorders; anxiety-related disorders; attention-related disorders; psychosis-related disorders; personality disorders; eating disorders; cognitive impairment (including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment; neuropathic pain; chronic muscle or bone pain; diabetic complications resulting in nerve injury; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; or a combination thereof.
  • TBI traumatic brain injury
  • non-TBI-related cognitive impairment including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment
  • neuropathic pain chronic muscle or bone pain
  • diabetic complications resulting in nerve injury generalized attack of muscular weakness
  • recurring sleep episodes during the day migraine
  • addiction or a combination thereof.
  • the invention comprises a deuterated GABA A5 -NAM compound according to Formula I: wherein R 1 , R 2 , and R 3 each independently are H or D, with the proviso that at least one of R 1 , R 2 and R 3 is D, and wherein R 4 and R 5 each independently are H or D.
  • the invention relates to a GABA A5 -NAM compound, which is (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone (RG-1662); which is deuterated.
  • the invention relates to a compound selected from the group consisting of (3-(4-fluophenyl)-5-(methyl-d3)isoxazol-4yl)methanol; 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4yl-methoxy)nicotinonitrile; and 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)nicotinic acid.
  • the deuterated GABA A5 -NAM compound is according to Formula II
  • the invention also comprises a deuterated Basmisanil-related or Basmisanil-derivative compound as discussed herein, which is synthesized by: (a) treating (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol with a base or under basic conditions in the presence of a deuterium donor or followed by a deuterium donor; (b) adding the product of step (a) to 6-chloronicotinonitrile or methyl 6-chloronicotinate; (c) hydrolyzing the product of step (b) to the carboxylic acid; and (d) amide coupling the product of step (c) with thiomorpholine 1,1-dioxide or a salt thereof.
  • the deuterium donor can be D 2 O or CD 3 OD.
  • the invention relates to a method of forming a deuterated RG-1662 compound comprising treating a compound selected from the group consisting of 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)nicotinonitrile; 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)nicotinamide; and 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)nicotinic acid, with base in the presence of a deuterium-containing solvent.
  • the deuterium-containing solvent is D 2 O.
  • Certain embodiments of the invention relate to a deuterated GABA A5 -NAM compound of claim 1 which has a longer biological half-life when administered to a mammal than a non-deuterated compound of the same structure.
  • a method of treating a depression-related disorder in a human subject in need thereof comprising administering a therapeutically effective amount of a deuterated GABA A5 -NAM compound as described herein to the subject.
  • the deuterated GABA A5 -NAM compound can be administered orally, intradermally, intramuscularly, intraperitoneally, intravenously, via insufflation, or in a dermal patch, and can be administered to the subject every 0.5, 1, 2, 3 or 4 days.
  • the method involves those wherein the deuterated GABA A5 -NAM compound is administered to the subject in combination with one or more additional therapies for the treatment or amelioration of depression.
  • these therapies can include, but are not limited to administration of an antidepressant drug selected from the group consisting of a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a triple reuptake inhibitor, a modulator of CNS acetylcholine function, a stimulant, an anti-glucocorticoids, an NMDA-type glutamate receptor antagonist, a tricylic antidepressants, and any combination thereof.
  • an antidepressant drug selected from the group consisting of a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a triple reuptake inhibitor, a modulator of
  • the depression-related disorder can be selected from one or more of general depression, major depressive disorder (clinical depression), dysthymia, suicidality, unipolar depression, bipolar depression, psychotic depression, atypical depression, seasonal affective disorder, premenstrual dysphoric disorder, endogenous depression, catatonic depression, post-traumatic stress disorder, postpartum depression, depression arising from illness or injury, depression arising from drugs or alcohol, treatment-resistant depression, and any combination thereof.
  • Other disorders and conditions included in the definition of depression-related disorders are those in with these symptoms occur as a secondary consequence of some other primary medical condition, such as a tumor, trauma, substance abuse disorder, alcoholism.
  • the deuterated GABA A5 -NAM compound is selected from the group consisting of (3-(4-fluophenyl)-5-(methyl-d3)isoxazol-4yl)methanol; 6-((3-(4-fluorophenyl)-5-(methyld3)isoxazol-4yl-methoxy)nicotinonitrile; 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)nicotinic acid; and (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)pyridine-3-yl)methanone.
  • the subject is a human.
  • deuterium refers to a stable isotope of hydrogen with a mass approximately twice of the most common isotope, i.e., a mass of about 2 atomic mass units.
  • biological half-life refers to the time that a living body requires to remove one half the quantity of an administered substance through normal elimination.
  • treating refers to an intervention in disease such as administration of a pharmaceutical composition to a subject in need.
  • Such treatment involves taking a step to obtain beneficial or desired results, including clinical results such as mitigating, alleviating or ameliorating one or more symptoms of a disease, disorder, or condition; diminishing the extent of the disease, disorder, or condition; delaying or slowing the progression of a disease, disorder, or condition; preventing or reducing the chance or frequency of recurrence of a disease, disorder, or condition; ameliorating or stabilizing a metric (statistic) of the disease, disorder, or condition; or promoting by direct or indirect means the efficacy of another medication with benefit in treating the disease, disorder, or condition.
  • beneficial or desired results including clinical results such as mitigating, alleviating or ameliorating one or more symptoms of a disease, disorder, or condition; diminishing the extent of the disease, disorder, or condition; delaying or slowing the progression of a disease, disorder, or condition; preventing or reducing the chance or frequency of recurrence of a disease
  • depression-related disorder includes any disorder causing, related to or defined by depression and any disorder or condition having depressive symptoms. As used herein, this term also includes cognitive, memory, substance abuse, and psychotic disorders. Depressive disorders include, but are not limited to general depression, major depressive disorder (clinical depression), dysthymia, suicidality, unipolar depression, bipolar depression, psychotic depression, atypical depression, seasonal affective disorder, premenstrual dysphoric disorder, endogenous depression, catatonic depression, posttraumatic stress disorder, postpartum depression, and any combination thereof.
  • depression-related disorders include anxiety-related disorders; anhedonia; attention-related disorders; psychosis-related disorders; personality disorders; sleep disorders; eating disorders; cognitive impairment (including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment; memory impairment; disorders of learning; neuropathic pain; chronic muscle or bone pain; diabetic neuropathy; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; or a combination thereof.
  • TBI traumatic brain injury
  • non-TBI-related cognitive impairment including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment; memory impairment; disorders of learning; neuropathic pain; chronic muscle or bone pain; diabetic neuropathy; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; or a combination thereof.
  • Other disorders and conditions included in the definition of depression-related disorders are those in with these symptoms occur as a secondary consequence of some other primary medical condition, such as a tumor, substance abuse disorder, alcoholism.
  • subject in need refers to any animal, preferably a mammal, and most preferably a human.
  • Laboratory animals, companion and service animals, farm animals, and zoo animals are included in this definition.
  • Preferred animals include mice, rats, rabbits, monkeys, apes, and humans.
  • terapéuticaally effective amount means an amount of a therapeutic agent, which, when administered to a subject, has the intended therapeutic effect.
  • a therapeutic effect is an effect that treats the intended disorder or condition, including improving the disease, disorder or condition, or a symptom thereof, including reduction of a symptom or delaying the onset or reoccurrence of the disease, disorder, condition, or symptom.
  • the full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the medical condition is a depression-related disorder; an anxiety-related disorder; an attention-related disorder; a psychosis-related disorder; a personality disorder; an eating disorder; cognitive impairment (including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment; neuropathic pain; chronic muscle or bone pain; diabetic complications resulting in nerve injury; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; alcoholism; substance use disorder; or any combination thereof.
  • TBI traumatic brain injury
  • non-TBI-related cognitive impairment including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment; neuropathic pain; chronic muscle or bone pain; diabetic complications resulting in nerve injury; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; alcoholism; substance use disorder; or any combination thereof.
  • TBI traumatic brain injury
  • non-TBI-related cognitive impairment including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment
  • references in this description to methods of treatment are to be interpreted as references to compounds and compositions for use in those methods.
  • Embodiments of the invention concern compositions and methods for the treatment of one or more medical conditions, in particular including depression and similar conditions.
  • the condition may be of any kind, but in specific embodiments the condition being treated is major depression (major depressive disorder) and/or suicidality.
  • treatment of the medical condition preferably occurs at a more rapid rate than currently known treatments for this type of illness, successfully treats a larger fraction of the patient population, and has fewer deleterious side effects.
  • one or more partial inverse agonists of the benzodiazepine binding site of GABA A receptors containing an ⁇ 5 subunit produce a rapid antidepressant action in unipolar and bipolar forms of depression and reduce suicidal ideation by restoring the normal function of excitatory synapses.
  • Such considerations may be characterized, by example, using rodent models of depression with face, construct, and predictive validity, such chronic unpredictable stress (CUS) or chronic multimodal stress (restraint, strobe light, and white noise), to characterize the actions of acute administration (24 hours) of ⁇ 5-selective GABA-NAMs.
  • CCS chronic unpredictable stress
  • strobe light strobe light
  • white noise chronic multimodal stress
  • Antidepressant efficacy of partial inverse agonists of ⁇ 5 subunit-containing GABA A receptors can be tested in vivo in laboratory animals, such as mice and rats, using the sucrose preference and social exploration tests (Amat et al., 2010), for example.
  • patients may undergo standard psychiatric screening for DSM-IV criteria for major depressive episodes.
  • a saline solution comprising one or more of the agonists are provided to the individual, such as infused slowly (ca. 30-60 min), for example.
  • Depression-related and other rating tests such as the Hamilton Depression Rating Scale, Beck Depression Inventory, Visual Analog Scales score for intoxication "high", and the Brief Psychiatric Rating Scale, may be given repeatedly; as an example only, they may be given over a four hour period after drug administration, and daily over the following seven days.
  • Antidepressant efficacy, as well as psychomimetic or anxiogenic responses, is determined upon changes in the test scores, in specific embodiments to show efficacy with a particular compound.
  • Specific embodiments of the invention involve negative allosteric modulators of alpha5 subunit-containing GABA A Rs, which are fast-acting antidepressants that address depression and/or reduce suicidality.
  • these modulators are novel deuterated compounds that offer discreet advantages over the non-deuterated modulators. These advantages can include prolonged bioavailability in the treated subject.
  • Deuterium is a naturally occurring, stable, non-radioactive isotope of hydrogen. Hydrogen consists of one electron surrounding a nucleus composed of one proton and has a mass of approximately 1.0 atomic mass unit (AMU). Deuterium also has a single electron but its nucleus contains one neutron and one proton, resulting in an atomic mass of approximately 2.0 AMU. When excess deuterium is incorporated into molecules in place of hydrogen, referred to as deuteration, the deuterated compound is similar to the all-hydrogen compound. In general, deuterated compounds have shapes and sizes that are essentially indistinguishable from their all-hydrogen analogues. Moreover, deuterium has remarkably low systemic toxicology.
  • Single celled organisms can often be grown in conditions of full deuteration.
  • humans can tolerate high levels of deuterium in body fluids.
  • deuterated compounds have a long history of safe use in humans as metabolic and pharmacokinetic probes. Selective deuteration can thus be used in pharmaceutical compounds and compositions to create new drugs, as herein described, that meet unmet medical needs.
  • Several deuterated drugs have entered into clinical evaluation. The first deuterated drug has been approved by the FDA (Austedo TM ; deutetrabazine) for Huntington's chorea.
  • GABA A alpha-5 negative allosteric modulators are shown to act as rapid antidepressants in several mouse models of depression.
  • a use patent was subsequently filed for the use of GABA A alpha5 NAMs as antidepressant agents.
  • GABA A alpha5 NAMs as antidepressant agents.
  • RG-1662 (1,1-Dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone
  • RG-1662 (1,1-Dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone
  • RG-1662 a GABA A alpha5-selective NAM which was shown to be safe (but not efficacious) in phase II clinical trials as a nootropic, was
  • the present invention relates to a composition and methods of using the composition for treating and/or ameliorating depression and/or suicidality in a human subject, and other depression-related disorders comprising administering to the subject a therapeutically effective amount of a deuterated negative allosteric modulator of GABA A Rs containing alpha5 subunits.
  • the modulator is a version of RG-1662), a GABA A5 R negative allosteric modulator (NAM) that has been previously shown to be safe in phase II clinical trials, which has been modified by substitution of deuterium for hydrogen atoms at one or more specific sites that are sites of hydrolysis in the liver in order to prolong its half-life in the human body.
  • Selective negative allosteric modulators for GABA A Rs containing alphas subunits can be modified by substituting deuterium ions for hydrogen ions at positions in the molecules that are substrates for hydrolysis by degradative liver enzymes. This modification slows down the compounds' rate of hydrolysis and catabolism in the body. This prolongs bioavailability of the compounds regardless of delivery route and increases their clinical utility as fast acting antidepressants.
  • the compounds according to the invention therefore are deuterated.
  • the deuterium content at any particular hydrogen atom in the compounds can range from no deuterium (or the natural abundance of deuterium), up to about 95% deuterium or more.
  • the hydrogen atoms that are the sites of hydrolysis in liver metabolism are enriched in deuterium. These sites were first identified in in vitro assays using cultured hepatocytes so as to be able to specifically direct their chemical substitution. When this deuteration procedure has been performed on RG-1662, this compound is referred to as NCGC-43 herein.
  • Preferred compounds are derived from GR-1662 and are selected from the group consisting of (3-(4-fluophenyl)-5-(methyl-d3)isoxazol-4yl)methanol; 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4yl-methoxy)nicotinonitrile; 6-((3-(4-fluorophenyl)-5-(methyld3)isoxazol-4-yl)methoxy)nicotinic acid; and (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)pyridine-3-yl)methanone (NCGC-43).
  • the deuterated alpha5 subunit-selective GABA-NAM compound is synthesized using the reaction/synthesis methods described in Example 1, and the deuterated compound characterized using
  • GABA-NAM compounds which preferably are deuterated, and most preferably are deuterated at the location where liver metabolism occurs in the compound.
  • the invention includes the intermediate compounds
  • the preferred compound is
  • the compounds of the invention include the base, and any pharmaceutically acceptable hydrate, solvate, acid or salt thereof, and can be amorphous or in any crystalline form, or as an oil or wax.
  • Any pharmaceutically acceptable salt can be used, as may be convenient. Generally, these salts are derived from pharmaceutically and biologically acceptable inorganic or organic acids and bases or metals.
  • salts include, but are not limited to: acetate, adipate, alginate, ammonium, aspartate, benzoate, benzenesulfonate (besylate), bicarbonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, carbonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, magnesium, maleate, malonate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pect
  • the compounds also include any or all stereochemical forms of the therapeutic agents (i.e., the R and/or S configurations for each asymmetric center). Therefore, single enantiomers, racemic mixtures, and diastereomers of the therapeutic agents are within the scope of the invention. Also within the scope of the invention are steric isomers and positional isomers of the therapeutic agents.
  • the compounds described herein are formulated and are administered as a pharmaceutical composition that includes a pharmaceutically acceptable carrier and one or more pharmaceutical agent, including one or more of the inventive compounds described herein, and including one or more of the inventive compounds described herein with an additional agent, such as an anticancer drug of another class.
  • a pharmaceutically acceptable carrier refers to any convenient compound or group of compounds that is not toxic and that does not destroy or significantly diminish the pharmacological activity of the therapeutic agent with which it is formulated.
  • Such pharmaceutically acceptable carriers or vehicles encompass any of the standard pharmaceutically accepted solid, liquid, or gaseous carriers known in the art, such as those discussed in the art.
  • a suitable carrier depends on the route of administration contemplated for the pharmaceutical composition. Routes of administration are determined by the person of skill according to convenience, the health and condition of the subject to be treated, and the location and stage of the condition to be treated.
  • routes of administration can include, but are not limited to local and parenteral, including oral, topical, transdermal, buccal, sublingual, transmucosal, wound covering, inhalation, insufflation, rectal, vaginal, nasal, wound covering, intravenous injection, intramuscular injection, intra-arterial injection, intrathecal injection, subcutaneous injection, intradermal injection, intraperitoneal injection, direct local injection, and the like.
  • the administration can be given by transfusion or infusion, and can be administered by an implant, an implanted pump, or an external pump, or any device known in the art.
  • the forms which the pharmaceutical composition can take will include, but are not limited to: tablets, capsules, caplets, lozenges, dragees, pills, granules, oral solutions, powders for dilution, powders for inhalation, vapors, gases, sterile solutions or other liquids for injection or infusion, transdermal patches, buccal patches, inserts and implants, rectal suppositories, vaginal suppositories, creams, lotions, oils, ointments, topical coverings (e.g., wound coverings and bandages), suspensions, emulsions, lipid vesicles, and the like.
  • Carriers can include, for example, starch (e.g., corn starch, potato starch, rice starch), celluloses (e.g., microcrystalline cellulose, methylcellulose, and the like), sugars (e.g., lactose, sucrose, glucose, fructose, and the like), clays, minerals (e.g., talc, and the like), gums, flavorings, odorants and fragrances, preservatives, colorings, taste-masking agents, sweeteners, gels, waxes, lipids (e.g., lipid vesicles or nanoparticles), oils, polyethylene glycols, glycerine, propylene glycol, solvents (e.g., water or pharmaceutically acceptable organic solvents), saline solutions (e.g., saline solutions, electrolyte solutions, lactated saline solutions, and
  • the compounds or pharmaceutical compositions containing the compounds can be provided in containers such as blister packs, ampoules, bottles, pre-filled syringes, and the like.
  • Extended and sustained release compositions also are contemplated for use with and in the inventive embodiments.
  • suitable carriers can include any of the known ingredients to achieve a delayed release, extended release or sustained release of the active components.
  • the pharmaceutical compositions comprise a therapeutically effective amount.
  • deuterated alpha5-selective GABA-NAMs such as NCGC-43 are administered to a human subject in a therapeutically effective amount by any convenient route of administration.
  • the dose of the inventive compound is administered to the subject at convenient intervals such as every 0.5, 1, 2, 3 or more days, weekly, or at any convenient interval, in repetitive dosing regimens.
  • the compound can be administered alone as a monotherapy, or in combination with one or more other therapies, either in the same dosage form or in separate dosage forms, provided at the same time or at different times, in single doses or in a repetitive dosing regimen.
  • Treatment regimens include a single administration or a course of administrations lasting two or more days, including a week, two weeks, several weeks, a month, 30 days, 60 days, 90 days, several months, six months, a year, or more, including administration for the remainder of the subject's life.
  • the regimen can include multiple doses per day, one dose per day or per week, for example, or a long infusion administration lasting for an hour, multiple hours, a full day, or longer.
  • Dosage amounts per administration include any amount determined by the practitioner, and will depend on the size of the subject to be treated, the state of the health of the subject, the route of administration, the condition to be treated or prevented, and the like. In general, it is contemplated that for the majority of subjects, a dose in the range of about 0.01 mg/kg to about 100 mg/kg is suitable, preferably about 0.1 mg/kg to about 50 mg/kg, more preferably about 0.1 mg/kg to about 10 mg/kg, and most preferably about 0.2 mg/kg to about 5 mg/kg are useful. This dose can be administered weekly, daily, or multiple times per day. A dose of about 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 250 mg, 500 mg, or 1000 mg can be administered.
  • a therapeutically effective dose results in the presence of the deuterated compounds in the cerebrospinal fluid of the subject at a concentration sufficient to bind to 10 to 75% of all GABA A R in order to reduce GABA A R function by at least about 10 to 75%.
  • preferred deuterated compositions have a long half-life when therapeutically administered to a mammal such as a human subject, including deuterated RG-1662 compounds in order to yield enhanced bioavailability and increased half-life when administered to a human subject.
  • the inventive methods involve administration of a therapeutically effective amount of deuterated alpha5 subunit-selective GABA-NAMs in combination (sequentially or concomitantly) with another antidepressant drug.
  • the antidepressant drugs can include, for example, one or more of a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a triple reuptake inhibitor, a CNS acetylcholine function modulator, a stimulant, an anti-glucocorticoid, an NMDA-type glutamate receptor antagonist, a tricylic antidepressant, a drug used to reduce craving and withdrawal in substance abuse disorder or alcoholism, and any combination thereof.
  • GABA A5 -NAM compounds of which RG-1662 is a member, have potential utility in treating psychiatric and neurological conditions such as Down's Syndrome, bipolar disorder, pathological anxiety, and autism spectrum disorders.
  • the invention relates to methods for treating, preventing, or ameliorating at least one symptom in an individual suffering from a depression related disorder as defined above.
  • the subjects contemplated as "in need” of the inventive methods refers to any animal, preferably a mammal, and most preferably a human patient suffering from a depression-related disorder, including any disorder causing, related to or defined by depression and any disorder or condition having depressive symptoms.
  • this term also includes cognitive, memory and psychotic disorders.
  • Depressive disorders include, but are not limited to general depression, major depressive disorder (clinical depression), dysthymia, suicidality, unipolar depression, bipolar depression, psychotic depression, atypical depression, seasonal affective disorder, premenstrual dysphoric disorder, endogenous depression, catatonic depression, post-traumatic stress disorder, postpartum depression, posttraumatic stress disorder, and any combination thereof.
  • depression-related disorders include anxiety-related disorders; anhedonia; attention-related disorders; psychosis-related disorders; personality disorders; sleep disorders; eating disorders; cognitive impairment (including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment; memory impairment; disorders of learning; neuropathic pain; chronic muscle or bone pain; diabetic neuropathy; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; or a combination thereof.
  • TBI traumatic brain injury
  • non-TBI-related cognitive impairment including that which follows traumatic brain injury (TBI) or non-TBI-related cognitive impairment; memory impairment; disorders of learning; neuropathic pain; chronic muscle or bone pain; diabetic neuropathy; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; or a combination thereof.
  • Other disorders and conditions included in the definition of depression-related disorders are those in with these symptoms occur as a secondary consequence of some other primary medical condition, such as a tumor, substance abuse disorder, alcoholism.
  • Such subjects are treated by administration of the deuterated RG-1662 compound NCGC-43 or composition in an amount of about 0.1 mg to about 1000 mg preferably administered about once per day, week, month, or on an as needed basis.
  • the preferred routes of administration are oral, topical, transdermal, buccal, sublingual, transmucosal, wound covering, inhalation, insufflation, rectal, vaginal, nasal, wound covering, intravenous injection, intramuscular injection, intra-arterial injection, intrathecal injection, subcutaneous injection, intradermal injection, intraperitoneal injection, direct local injection, and the like.
  • the administration can be given by transfusion or infusion, and can be administered by an implant, an implanted pump, or an external pump, or any device known in the art.
  • NCGC00508843 was synthesized from (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol as follows. Treatment of (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol with sodium deuteroxide in a mixture of deuterium oxide and deuterated methanol at elevated temperature yielded (3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methanol.
  • the deuterated compounds were synthesized from RG-1662 to produce (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)pyridin-3-yl)methanone (NCGC00508843; NCGC-43) in four steps from commercial materials, with a 33% overall yield. Deuterium incorporation was measured By 1 H NMR to be 95%.
  • 6-((3-(4-Fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)nicotinonitrile was synthesized as follows. Sodium hydride (120 mg, 2.9 mmol, 60% dispersion in mineral oil) was added to a solution of (3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methanol (504 mg, 2.4 mmol) in tetrahydrofuran (THF) (5.0 mL) at 0°C. Then, a solution of 6-chloroniconinonitrile (400 mg, 2.9 mmol) in THF (5.0 mL) was added via syringe.
  • THF tetrahydrofuran
  • 6-((3-(4-Fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)nicotinic acid was synthesized as follows. Deuterium oxide (5.0 ml) and sodium deuteroxide (2.5 g, 18 mmol, 30% weight in D 2 O) was added to a vial containing a solution of 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)nicotinonitrile (560 mg, 1.8 mmol)) in d4-methanol (7.0 mL). The vial was sealed, and the reaction was heated to 55 °C and stirred for 16 hours.
  • FIG. 2 shows a comparison of NCGC-43 and ketamine in the sucrose preference test demonstrating the ketamine-like fast and persistent antidepressant effect of NCGC-43.
  • rats were given an overnight two bottle choice task (in which the sucrose solution consumption is shown as a percentage of the total solution consumed) before commencing stress (baseline), immediately after 14 days of chronic multimodal stress, and 24 hours, 7 days, and 14 days after an injection of NCGC-43 (3 mg/kg, gray), ketamine (20 mg/kg, orange), or vehicle (DMSO solution, blue), all while continuing with daily chronic multimodal stress.
  • a control group received neither stress nor drug (yellow).
  • Chronic stress decreased sucrose preference, a sign of anhedonia, whereas a single injection of ketamine or NCGC-43 restored sucrose preference in a rapid (within 24 hours) and persistent (up to 14 days) manner.
  • NCGC-43 The effects of NCGC-43 were comparable to ketamine, which is known to produce rapid and persistent antidepressant effects in humans.
  • FIG. 3 shows a comparison of NCGC-43 and ketamine in the social interaction test demonstrating the ketamine-like fast and persistent antidepressant effect of NCGC-43.
  • rats were given a choice between spending time in a chamber with a novel caged juvenile rat and a chamber with an empty cage.
  • rats were given a choice between spending time in a chamber with a novel caged juvenile rat and a chamber with an empty cage before commencing stress (baseline), immediately after 14 days of chronic multimodal stress, and 24 hours after an injection of NCGC-43 (3 mg/kg, gray), ketamine (20 mg/kg, orange), or vehicle (DMSO solution, blue).
  • Social interaction computed as percent time spent with the novel animal.
  • a control group received neither stress nor drug (yellow). Chronic stress decreased social interactions, a sign of anhedonia, whereas a single injection of ketamine or NCGC-43 restored their preference for interacting with a novel animal.
  • FIG. 4 shows the effects of NCGC-43 in the open field test.
  • FIG. 4A is a schematic of the open field test.
  • FIG. 4B shows that neither chronic stress nor injection of NCGC-43 or vehicle had any significant effects on overall locomotor activity.
  • FIG. 4C shows that neither chronic stress nor injection of NCGC-43 or vehicle had any significant effects on the time the animal spent in the corners and sides during the testing procedures, consistent with no change in the animals' state of anxiety under any condition.
  • FIG. 4D shows that neither chronic stress nor injection of NCGC-43 or vehicle had any significant effects on the ratio of the time the animal spent in the center of the chamber to the time spent in the corners/sides during the testing procedures, consistent with no change in the animals' state of anxiety under any condition.
  • FIG. 4A is a schematic of the open field test.
  • FIG. 4B shows that neither chronic stress nor injection of NCGC-43 or vehicle had any significant effects on overall locomotor activity.
  • FIG. 4C shows that neither chronic stress nor injection of NCGC-43 or
  • NCGC-43 did not affect the latency before the animals first entered the center of the chamber, consistent with no change in the animals' state of anxiety, whereas NCGC-43 mildly decreased the latency, consistent with a modest anxiolytic effect.
  • Behavioral measurements were made before commencing stress (baseline), immediately after 14 days of chronic multimodal stress, and 24 hours after an injection of NCGC-43 (3 mg/kg) or vehicle (DMSO solution).
  • FIG. 5 shows a comparison of NCGC-43 and ketamine in the elevated plus maze, demonstrating the lack of an anxiolytic response to NCGC-43.
  • rats were given a choice between spending time in one of two arms of an elevated cross-shaped maze (one arm closed and the other arm open), immediately after 14 days of chronic multimodal stress, and 24 hours after an injection of NCGC-43 (3 mg/kg) or ketamine (20 mg/kg).
  • a control group was unstressed and received a vehicle injection (DMSO).
  • DMSO vehicle injection
  • a single injection of ketamine increased the percent of time the rat spent in the closed arm, consistent with an increase in anxiety or fear. Neither stress nor NCGC nor vehicle injection had an effect on time spent in the closed arm, consistent that they did not increase anxiety or fear.
  • FIG. 6 shows a comparison of NCGC-43 and ketamine in the forced swim test.
  • naive rats and rats subjected to 14 days of chronic multimodal stress are placed in a water-filled tank (for 5 minutes), 1 hour or 24 hours after an injection of NCGC-43 (3 mg/kg), ketamine (20 mg/kg), or vehicle (DMSO solution), and monitored for the time the animals spent immobile ( Fig. 6A ) and the latency until the animals ceased to struggle and become immobile ( Fig. 6B ), behavioral responses that are said to be rodent analogs of "behavioral despair.”
  • Twenty-four hours after NCGC-43 and ketamine injection there was a decrease in the time the animals spent immobile ( Fig.
  • NCGC-43 and ketamine both exert an antidepressant-like response in this test. Comparison of responses at 1 hour and 24 hours suggest that NCGC-43 exerts rapid and persistent effects similar to those described previously for ketamine (Zanos et al., 2016). See also FIG. 6C and FIG. 6D .
  • FIG. 7 shows the dose-response relationship of NCGC-43 in the forced swim test.
  • the liver is the major metabolic organ within mammals. Basmisanil is metabolized as follows.
  • Table 1 presents data regarding the half-life of RG-1622 in rat and human liver hepatocytes, in vitro, showing an increase in half-life for the deuterated compounds. Stability improved more in human hepatocytes compared to rat hepatocytes, with variation between the hepatocyte studies.
  • the deuterated RG-1662 compound therefore is more metabolically stable. Longer half-life also allows less frequent dosing.
  • Preferred compounds are more potent and effective, and preferably are deuterated. Deuteration preferably is located at the site of metabolism, since installing deuterium atoms at the site of metabolism more readily increases the half-life of the compound. Table 1. Half-Life of RG-1662 Compounds in Hepatocytes In Vitro.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Psychiatry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (18)

  1. Composé GABAA5-NAM deutéré selon la Formule I :
    Figure imgb0023
    dans lequel R1, R2 et R3 sont chacun indépendamment H ou D, sous réserve que au moins un de R1, R2 et R3 soit D, et
    dans lequel R4 et R5 sont chacun indépendamment H ou D.
  2. Composé GABAA5-NAM deutéré selon la revendication 1, dans lequel R4 et R5 sont H.
  3. Composé GABAA5-NAM, qui est la (1,1-dioxydothiomorpholino)(6-((3-(4-fluorophényl)-5-méthylisoxazol-4-yl)méthoxy)pyridin-3-yl)méthanone (RG-1662), qui est deutérée.
  4. Composé choisi dans le groupe constitué de :
    a. (3-(4-fluorophényl)-5-(méthyl-d3)isoxazol-4-yl)méthanol ;
    b. 6-((3 -(4-fluorophényl)-5 -(méthyl-d3)isoxazol-4-yl)méthoxy)nicotinonitrile ; et
    c. acide 6-((3-(4-fluorophényl)-5-(méthyl-d3)isoxazol-4-yl)méthoxy)nicotinique.
  5. Composé GABAA5-NAM deutéré selon la revendication 1 selon la Formule II :
    Figure imgb0024
  6. Procédé de synthèse d'un composé Basmisanil deutéré selon la revendication 1, comprenant :
    (a) le traitement de (3-(4-fluorophényl)-5-méthylisoxazol-4-yl)méthanol avec une base ou dans des conditions basiques en présence d'un donneur de deutérium ou suivie par un donneur de deutérium ;
    (b) l'ajout du produit de l'étape (a) à du 6-chloronicotinonitrile ou du 6-chloronicotinate de méthyle ;
    (c) l'hydrolyse du produit de l'étape (b) en acide carboxylique ; et
    (d) le couplage amidique du produit de l'étape (c) avec du 1,1-dioxyde de thiomorpholine ou un sel de celui-ci.
  7. Procédé selon la revendication 6, dans lequel le donneur de deutérium est D2O ou CD3OD.
  8. Procédé de formation d'un composé RG-1662 deutéré comprenant le traitement d'un composé choisi dans le groupe constitué de :
    6-((3-(4-fluorophényl)-5-méthylisoxazol-4-yl)méthoxy)nicotinonitrile ;
    6-((3-(4-fluorophényl)-5-méthylisoxazol-4-yl)méthoxy)nicotinamide ; et
    acide 6-((3-(4-fluorophényl)-5-méthylisoxazol-4-yl)méthoxy)nicotinique
    avec une base en présence d'un solvant contenant du deutérium.
  9. Procédé selon la revendication 8, dans lequel le solvant contenant du deutérium est D2O.
  10. Composé GABAA5-NAM deutéré selon la revendication 1, qui a une demi-vie biologique plus longue lorsqu'il est administré à un mammifère qu'un composé non deutéré de la même structure.
  11. Composé GABAA5-NAM deutéré selon l'une quelconque des revendications 1, 2 et 5 pour utilisation dans une méthode de traitement d'un trouble lié à une dépression chez un sujet humain en ayant besoin, comprenant l'administration d'une quantité thérapeutiquement efficace du composé GABAA5-NAM deutéré au sujet.
  12. Composé pour utilisation selon la revendication 11, où le composé GABAA5-NAM deutéré est administré par voie orale, intradermique, intramusculaire, intrapéritonéale, intraveineuse, via une insufflation ou dans un patch dermique.
  13. Composé pour utilisation selon la revendication 11, où le composé GABAA5-NAM deutéré est administré au sujet tous les 0,5, 1, 2, 3 ou 4 jours.
  14. Composé pour utilisation selon la revendication 11, où le composé GABAA5-NAM deutéré est administré au sujet en combinaison avec une ou plusieurs thérapies supplémentaires pour le traitement ou l'amélioration d'une dépression.
  15. Composé pour utilisation selon la revendication 14, où les une ou plusieurs thérapies supplémentaires comprennent l'administration d'un médicament antidépresseur choisi dans le groupe constitué d'un inhibiteur de monoamine oxydase, d'un inhibiteur du recaptage sélectif de la sérotonine, d'un inhibiteur du recaptage de la sérotoninenorépinéphrine, d'un inhibiteur de recaptage triple, d'un modulateur de la fonction d'acétylcholine du CNS, d'un stimulant, d'un anti-glucocorticoïde, d'un antagoniste du récepteur de glutamate de type NMDA, d'un antidépresseur tricyclique et d'une quelconque combinaison de ceux-ci.
  16. Composé pour utilisation selon la revendication 11, où le trouble lié à une dépression est choisi dans le groupe constitué d'une dépression générale, d'un trouble dépressif majeur (dépression clinique), d'une dysthymie, d'un état suicidaire, d'une dépression unipolaire, d'une dépression bipolaire, d'une dépression psychotique, d'une dépression atypique, d'un trouble affectif saisonnier, d'un trouble dysphorique prémenstruel, d'une dépression endogène, d'une dépression catatonique, d'un trouble de stress post-traumatique, d'une dépression postpartum, d'une dépression découlant d'une maladie ou d'une blessure, d'une dépression découlant de médicaments ou de l'alcool, d'une dépression résistant au traitement et d'une quelconque combinaison de ceux-ci.
  17. Composé pour utilisation selon la revendication 16, où le trouble lié à une dépression est choisi dans le groupe constitué de ceux qui se produisent comme une conséquence secondaire d'un autre état médical principal choisi dans le groupe constitué d'une tumeur, d'un traumatisme, d'un trouble d'abus de substance et d'alcoolisme.
  18. Composé pour utilisation selon la revendication 11, où le composé GABAA5-NAM deutéré est choisi dans le groupe constitué de : (3-(4-fluorophényl)-5-(méthyld3)isoxazol-4-yl)méthanol ; 6-((3-(4-fluorophényl)-5-(méthyl-d3)isoxazol-4-yl)méthoxy)nicotinonitrile ; acide 6-((3-(4-fluorophényl)-5-(méthyl-d3)isoxazol-4-yl)méthoxy)nicotinique ; et (1,1-dioxydothiomorpholino)(6-((3-(4-fluorophényl)-5-(méthyl-d3)isoxazol-4-yl)méthoxy)pyridin-3-yl)méthanone.
EP18852438.3A 2017-08-28 2018-08-28 Nouveaux modulateurs du récepteur de l'acide gamma-aminobutyrique de type a destinés aux troubles de l'humeur Active EP3675845B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762550826P 2017-08-28 2017-08-28
PCT/US2018/048339 WO2019046300A1 (fr) 2017-08-28 2018-08-28 Nouveaux modulateurs du récepteur de l'acide gamma-aminobutyrique de type a destinés aux troubles de l'humeur

Publications (3)

Publication Number Publication Date
EP3675845A1 EP3675845A1 (fr) 2020-07-08
EP3675845A4 EP3675845A4 (fr) 2021-05-05
EP3675845B1 true EP3675845B1 (fr) 2024-07-17

Family

ID=65525999

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18852438.3A Active EP3675845B1 (fr) 2017-08-28 2018-08-28 Nouveaux modulateurs du récepteur de l'acide gamma-aminobutyrique de type a destinés aux troubles de l'humeur

Country Status (12)

Country Link
US (2) US11459320B2 (fr)
EP (1) EP3675845B1 (fr)
JP (2) JP7403050B2 (fr)
KR (1) KR20200044906A (fr)
CN (1) CN111201016A (fr)
AU (1) AU2018323443B2 (fr)
BR (1) BR112020004116A2 (fr)
CA (1) CA3074110A1 (fr)
EA (1) EA202090521A1 (fr)
ES (1) ES2987108T3 (fr)
MX (1) MX2020002196A (fr)
WO (1) WO2019046300A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2020002196A (es) 2017-08-28 2020-09-28 Univ Maryland Moduladores receptores de tipo a de ácido gammaaminobutírico novedosos para trastornos del humor.
IL297861A (en) * 2020-05-08 2023-01-01 Psilera Inc Novel compositions of matter and pharmaceutical compositions
AU2022270411A1 (en) 2021-05-05 2023-11-23 Draig Therapeutics Ltd Heteroaryl compounds useful in the treatment of cognitive disorders

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4783375B2 (ja) * 2004-10-20 2011-09-28 エフ．ホフマン−ラ ロシュ アーゲー イミダゾベンゾジゼピン誘導体
NZ585308A (en) * 2007-12-04 2012-03-30 Hoffmann La Roche Isoxazolo-pyridine derivatives
US8222246B2 (en) * 2009-04-02 2012-07-17 Hoffmann-La Roche Inc. Substituted isoxazoles
US8604062B2 (en) * 2011-10-20 2013-12-10 Hoffman-La Roche Inc. Process for the preparation of isoxazolyl-methoxy nicotinic acids
US8785435B2 (en) 2011-10-20 2014-07-22 Hoffmann-La Roche Inc. Solid forms
EP3125902B1 (fr) 2014-03-31 2020-09-16 University of Maryland, Baltimore Utilisation de modulateurs négatifs des récepteurs gaba contenant des sous-unités alpha5 comme antidépresseurs à action rapide
EP4512394A3 (fr) * 2015-06-03 2025-10-22 Triastek, Inc. Formes galéniques et leur utilisation
CA2968836C (fr) * 2016-06-13 2025-09-02 Gilead Sciences Inc Composes modulant fxr (nr1h4)
MX2020002196A (es) 2017-08-28 2020-09-28 Univ Maryland Moduladores receptores de tipo a de ácido gammaaminobutírico novedosos para trastornos del humor.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHAO ET AL: "The kinetic isotope effect in the search for deuterated drugs", DRUG NEWS AND PERSPECTIVES, PROUS SCIENCE, ES, vol. 23, no. 6, 1 January 2010 (2010-01-01), pages 398 - 404, XP009139025, ISSN: 0214-0934 *

Also Published As

Publication number Publication date
JP7749896B2 (ja) 2025-10-07
WO2019046300A9 (fr) 2020-10-15
US20200199119A1 (en) 2020-06-25
CA3074110A1 (fr) 2019-03-07
ES2987108T3 (es) 2024-11-13
EA202090521A1 (ru) 2020-06-10
CN111201016A (zh) 2020-05-26
US11459320B2 (en) 2022-10-04
JP2021500309A (ja) 2021-01-07
BR112020004116A2 (pt) 2020-09-01
EP3675845A1 (fr) 2020-07-08
US11897875B2 (en) 2024-02-13
EP3675845A4 (fr) 2021-05-05
WO2019046300A1 (fr) 2019-03-07
KR20200044906A (ko) 2020-04-29
JP2023133571A (ja) 2023-09-22
MX2020002196A (es) 2020-09-28
JP7403050B2 (ja) 2023-12-22
AU2018323443A1 (en) 2020-03-12
US20220396572A1 (en) 2022-12-15
AU2018323443B2 (en) 2024-09-05

Similar Documents

Publication Publication Date Title
US11897875B2 (en) Deuterated Alpha5 subunit-selective negative allosteric modulators of gamma-aminobutyric acid type a receptors as fast acting treatment for depression and mood disorders
US20240000765A1 (en) Combination treatment of liver disorders
JP4993523B2 (ja) ２０（ｓ）−プロトパナキサジオールの抗うつ薬製造への使用
HUE034615T2 (en) New therapeutic approaches for treating parkinson's disease
JP2017537129A (ja) 選択的ｓ１ｐ１レセプターアゴニストを含む薬学的合剤
WO2021231644A1 (fr) Polythérapies contre des troubles hépatiques
US20090275597A1 (en) Methods of treating cns disorders
JP2014530835A (ja) Ｓ１ｐ受容体モジュレーターまたはｓ１ｐ受容体アゴニストのための投薬量レジメン
CN113301894A (zh) mGluR5拮抗剂用于治疗阿片类物质镇痛耐受性的用途
WO2010126527A1 (fr) Méthodes de traitement des affections du snc
US20200276186A1 (en) Use of morphinans for treating cocaine addiction, pruritis, and seizure disorders
EA041547B1 (ru) Модуляторы рецептора гамма-аминомасляной кислоты типа a против расстройств настроения
AU2024204318A1 (en) Treatment of Post-Traumatic Syndrome Disorder
HK40034983A (en) Treatment of post-traumatic syndrome disorder
AU2019273656A1 (en) Pharmaceutical compounds for use in treating Huntington's disease
CN111670041A (zh) 用在组合疗法(睡眠障碍或中枢神经系统障碍)中的nmda受体调节剂(拉帕斯汀)组合
EP3436024A1 (fr) Dérivés non bioconvertibles substitués en c3 de la pregnénolone pour utilisation dans le traitement de la dépression réfractaire au traitement

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200227

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

RIN1 Information on inventor provided before grant (corrected)

Inventor name: VAN DYKE, ADAM

Inventor name: THOMPSON, SCOTT

Inventor name: MORRIS, PATRICK

Inventor name: THOMAS, CRAIG

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Free format text: PREVIOUS MAIN CLASS: A61K0031192000

Ipc: A61K0031185000

Ref country code: DE

Ref legal event code: R079

Ref document number: 602018071984

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A61K0031192000

Ipc: A61K0031185000

A4 Supplementary search report drawn up and despatched

Effective date: 20210406

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/185 20060101AFI20210330BHEP

Ipc: A61K 31/42 20060101ALI20210330BHEP

Ipc: A61K 31/53 20060101ALI20210330BHEP

Ipc: A61K 31/541 20060101ALI20210330BHEP

Ipc: A61K 31/5517 20060101ALI20210330BHEP

Ipc: A61K 9/20 20060101ALI20210330BHEP

Ipc: C07D 261/08 20060101ALI20210330BHEP

Ipc: C07D 413/12 20060101ALI20210330BHEP

Ipc: C07D 417/14 20060101ALI20210330BHEP

Ipc: A61P 25/24 20060101ALI20210330BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20230510

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Free format text: PREVIOUS MAIN CLASS: A61K0031185000

Ipc: A61K0031440200

Ref country code: DE

Ref legal event code: R079

Ref document number: 602018071984

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A61K0031185000

Ipc: A61K0031440200

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/19 20060101ALI20240124BHEP

Ipc: A61P 25/24 20060101ALI20240124BHEP

Ipc: C07D 417/14 20060101ALI20240124BHEP

Ipc: C07D 413/12 20060101ALI20240124BHEP

Ipc: C07D 261/08 20060101ALI20240124BHEP

Ipc: A61K 9/20 20060101ALI20240124BHEP

Ipc: A61K 45/06 20060101ALI20240124BHEP

Ipc: A61K 31/5517 20060101ALI20240124BHEP

Ipc: A61K 31/541 20060101ALI20240124BHEP

Ipc: A61K 31/53 20060101ALI20240124BHEP

Ipc: A61K 31/42 20060101ALI20240124BHEP

Ipc: A61K 31/185 20060101ALI20240124BHEP

Ipc: A61K 31/4402 20060101AFI20240124BHEP

INTG Intention to grant announced

Effective date: 20240207

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20240523

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602018071984

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2987108

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20241113

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241118

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1703500

Country of ref document: AT

Kind code of ref document: T

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241118

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241017

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241018

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241117

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241017

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241017

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241017

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241117

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20241018

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240828

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602018071984

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240831

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20250422

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20240831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240828

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20240717

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20250901

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20250827

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20250827

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20250825

Year of fee payment: 8